International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

H7. Generation of Novel Developmental Abnormalities using ENU Mutagenesis

Bruce Herron, Kimberly Simms, Heiko Peters, Weining Lu, Shanming Liu, Monica Justice1, David MacDonald2, David Beier
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
Baylor University Medical Center, Houston TX;
Wichita State University, Wichita, KA.

The generation of mouse models of human congential malformation syndromes can be useful both for the identification of genes important to mammalian development and for understanding the molecular basis of birth defects. We are presently using a systematic approach to screen mouse embryos derived from mice mutagenized with N-ethyl-nitrosourea (ENU) for recessive phenotypes similar to human congenital defects.

Our strategy uses a backcross breeding scheme in which third generation progeny are evaluated for developmental abnormalities at embryonic d18.5. In this manner we identify defects in organogenesis that are consistent with survival in utero to nearly full term, but which may cause post-natal lethality. Affected progeny from these lines are used directly in genetic mapping utilizing our previously described method of interval haplotype analysis (Neuhaus and Beier, Mamm. Genome 1998; 9:150-154). With this strategy, we are able to localize the mutation to a single linkage group by genotyping 9-10 probands using only 60 markers.

The main component of the mutation screen is a gross assessment of major organs after embryo dissection. A more detailed analysis for craniofacial abnormalities, kidney and brain abnormalities (by histological examination), and skeletal abnormalities (by cartilage and bone staining) are also performed. Our screening employs a hierarchical strategy in which each familial cohort is analyzed for abnormalities in at least 3 litters. Examining 3-6 additional litters for reproducibility of the phenotype further tests families for which a significant anomaly is found (about 50%). The yield of abnormal phenotypes that appear to segregate in a Mendelian fashion is presently 20% of fully tested families.

The spectrum of abnormal phenotypes found to date is remarkably varied, and includes developmental disorders of heart, palate, pancreas, kidney, skeleton, muscle and brain. Many of these disorders are similar to human malformation syndromes. Our results demonstrate that a recessive screen can be extremely productive for the purpose of generating abnormal developmental phenotypes and can be readily managed even in a small laboratory.

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